Neurobiology of Inflammation-Associated Anorexia

Compelling data demonstrate that inflammation-associated anorexia directly results from the action of pro-inflammatory factors, primarily cytokines and prostaglandins E2, on the nervous system. For instance, the aforementioned pro-inflammatory factors can stimulate the activity of peripheral sensory neurons, and induce their own de novo synthesis and release into the brain parenchyma and cerebrospinal fluid. Ultimately, it results in the mobilization of a specific neural circuit that shuts down appetite. The present article describes the different cell groups and neurotransmitters involved in inflammation-associated anorexia and examines how they interact with neural systems regulating feeding such as the melanocortin system. A better understanding of the neurobiological mechanisms underlying inflammation-associated anorexia will help to develop appetite stimulants for cancer and AIDS patients

Cognitive and Emotional Alterations Are Related to Hippocampal Inflammation in a Mouse Model of Metabolic Syndrome

Converging clinical data suggest that peripheral inflammation is likely involved in the pathogenesis of the neuropsychiatric symptoms associated with metabolic syndrome (MetS). However, the question arises as to whether the increased prevalence of behavioral alterations in MetS is also associated with central inflammation, i.e. cytokine activation, in brain areas particularly involved in controlling behavior. To answer this question, we measured in a mouse model of MetS, namely the diabetic and obese db/db mice, and in their healthy db/+ littermates emotional behaviors and memory performances, as well as plasma levels and brain expression (hippocampus; hypothalamus) of inflammatory cytokines. Our results shows that db/db mice displayed increased anxiety-like behaviors in the open-field and the elevated plus-maze (i.e. reduced percent of time spent in anxiogenic areas of each device), but not depressive-like behaviors as assessed by immobility time in the forced swim and tail suspension tests. Moreover, db/db mice displayed impaired spatial recognition memory (hippocampus-dependent task), but unaltered object recognition memory (hippocampus-independent task). In agreement with the well-established role of the hippocampus in anxiety-like behavior and spatial memory, behavioral alterations of db/db mice were associated with increased inflammatory cytokines (interleukin-1β, tumor necrosis factor-α and interleukin-6) and reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus but not the hypothalamus. These results strongly point to interactions between cytokines and central processes involving the hippocampus as important contributing factor to the behavioral alterations of db/db mice. These findings may prove valuable for introducing novel approaches to treat neuropsychiatric complications associated with MetS

Impaired Interleukin-1β and c-Fos Expression in the Hippocampus Is Associated with a Spatial Memory Deficit in P2X7 Receptor-Deficient Mice

Recent evidence suggests that interleukin-1β (IL-1β), which was originally identified as a proinflammatory cytokine, is also required in the brain for memory processes. We have previously shown that IL-1β synthesis in the hippocampus is dependent on P2X7 receptor (P2X7R), which is an ionotropic receptor of ATP. To substantiate the role of P2X7R in both brain IL-1β expression and memory processes, we examined the induction of IL-1β mRNA expression in the hippocampus of wild-type (WT) and homozygous P2X7 receptor knockout mice (P2X7R−/−) following a spatial memory task. The spatial recognition task induced both IL-1β mRNA expression and c-Fos protein activation in the hippocampus of WT but not of P2X7R−/− mice. Remarkably, P2X7R−/− mice displayed spatial memory impairment in a hippocampal-dependant task, while their performances in an object recognition task were unaltered. Taken together, our results show that P2X7R plays a critical role in spatial memory processes and the associated hippocampal IL-1β mRNA synthesis and c-Fos activation

Short-Term Long Chain Omega3 Diet Protects from Neuroinflammatory Processes and Memory Impairment in Aged Mice

Regular consumption of food enriched in omega3 polyunsaturated fatty acids (ω3 PUFAs) has been shown to reduce risk of cognitive decline in elderly, and possibly development of Alzheimer's disease. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are the most likely active components of ω3-rich PUFAs diets in the brain. We therefore hypothesized that exposing mice to a DHA and EPA enriched diet may reduce neuroinflammation and protect against memory impairment in aged mice. For this purpose, mice were exposed to a control diet throughout life and were further submitted to a diet enriched in EPA and DHA during 2 additional months. Cytokine expression together with a thorough analysis of astrocytes morphology assessed by a 3D reconstruction was measured in the hippocampus of young (3-month-old) and aged (22-month-old) mice. In addition, the effects of EPA and DHA on spatial memory and associated Fos activation in the hippocampus were assessed. We showed that a 2-month EPA/DHA treatment increased these long-chain ω3 PUFAs in the brain, prevented cytokines expression and astrocytes morphology changes in the hippocampus and restored spatial memory deficits and Fos-associated activation in the hippocampus of aged mice. Collectively, these data indicated that diet-induced accumulation of EPA and DHA in the brain protects against neuroinflammation and cognitive impairment linked to aging, further reinforcing the idea that increased EPA and DHA intake may provide protection to the brain of aged subjects

Microbiota-derived metabolites as drivers of gut-brain communication

Alterations in the gut microbiota composition have been associated with a range of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. The gut microbes transform and metabolize dietary- and host-derived molecules generating a diverse group of metabolites with local and systemic effects. The bi-directional communication between brain and the microbes residing in the gut, the so-called gut-brain axis, consists of a network of immunological, neuronal, and endocrine signaling pathways. Although the full variety of mechanisms of the gut-brain crosstalk is yet to be established, the existing data demonstrates that a single metabolite or its derivatives are likely among the key inductors within the gut-brain axis communication. However, more research is needed to understand the molecular mechanisms underlying how gut microbiota associated metabolites alter brain functions, and to examine if different interventional approaches targeting the gut microbiota could be used in prevention and treatment of neurological disorders, as reviewed herein.Abbreviations:4-EPS 4-ethylphenylsulfate; 5-AVA(B) 5-aminovaleric acid (betaine); Aβ Amyloid beta protein; AhR Aryl hydrocarbon receptor; ASD Autism spectrum disorder; BBB Blood–brain barrier; BDNF Brain-derived neurotrophic factor; CNS Central nervous system; GABA ɣ-aminobutyric acid; GF Germ-free; MIA Maternal immune activation; SCFA Short-chain fatty acid; 3M-4-TMAB 3-methyl-4-(trimethylammonio)butanoate; 4-TMAP 4-(trimethylammonio)pentanoate; TMA(O) Trimethylamine(-N-oxide); TUDCA Tauroursodeoxycholic acid; ZO Zonula occludens proteins</p

Neuroinflammatory processes in cognitive disorders:Is there a role for flavonoids and n-3 polyunsaturated fatty acids in counteracting their detrimental effects?

Neuroinflammatory processes are known to contribute to the cascade of events culminating in the neuronal damage that underpins neurodegenerative disorders such as Parkinson's and Alzheimer's disease. With the ageing population and increased cases of neurodegenerative diseases, there is a crucial need for the development of new strategies capable to prevent, delay the onset or treat brain dysfunction and associated cognitive decline. Growing evidence sheds light on the use of dietary polyphenols and n-3 long chain polyunsaturated fatty acids to improve cognitive performances and reduce the neuroinflammatory and oxidative stress responses occurring with age and neurodegenerative pathologies. This review will summarise the most recent information related to the impact and mechanisms underlying the neuroinflammatory processes in neurodegenerative disorders. We will also detail the current evidence indicating that flavonoids and n-3 polyunsaturated fatty acids are strong candidate in preventing neuroinflammation and modulating age-related memory decline, and will describe the potential mechanisms of action underlying their neuroprotective effects. As such, these dietary bioactives represent important precursor molecules in the quest to develop of a new generation of drugs capable of counteracting neuroinflammation and neurodegenerative diseases

Tetracosahexaenoylethanolamide, a novel -acylethanolamide, is elevated in ischemia and increases neuronal output.

-acylethanolamines (NAEs) are endogenous lipid-signaling molecules derived from fatty acids that regulate numerous biological functions, including in the brain. Interestingly, NAEs are elevated in the absence of fatty acid amide hydrolase (FAAH) and following CO-induced ischemia/hypercapnia, suggesting a neuroprotective response. Tetracosahexaenoic acid (THA) is a product and precursor to DHA; however, the NAE product, tetracosahexaenoylethanolamide (THEA), has never been reported. Presently, THEA was chemically synthesized as an authentic standard to confirm THEA presence in biological tissues. Whole brains were collected and analyzed for unesterified THA, total THA, and THEA in wild-type and FAAH-KO mice that were euthanized by either head-focused microwave fixation, CO + microwave, or CO only. PPAR activity by transient transfection assay and ex vivo neuronal output in medium spiny neurons (MSNs) of the nucleus accumbens by patch clamp electrophysiology were determined following THEA exposure. THEA in the wild-type mice was nearly doubled ( 0.05) transcriptional activity of PPARs relative to control, but 100 nM of THEA increased ( < 0.001) neuronal output in MSNs of the nucleus accumbens. Here were identify a novel NAE, THEA, in the brain that is elevated upon ischemia/hypercapnia and by KO of the FAAH enzyme. While THEA did not activate PPAR, it augmented the excitability of MSNs in the nucleus accumbens. Overall, our results suggest that THEA is a novel NAE that is produced in the brain upon ischemia/hypercapnia and regulates neuronal excitation

In silico Hierarchical Clustering of Neuronal Populations in the Rat Ventral Tegmental Area Based on Extracellular Electrophysiological Properties.

The ventral tegmental area (VTA) is a heterogeneous brain region, containing different neuronal populations. During recordings, electrophysiological characteristics are classically used to distinguish the different populations. However, the VTA is also considered as a region harboring neurons with heterogeneous properties. In the present study, we aimed to classify VTA neurons using approaches, in an attempt to determine if homogeneous populations could be extracted. Thus, we recorded 291 VTA neurons during extracellular recordings in anesthetized rats. Initially, 22 neurons with high firing rates (>10 Hz) and short-lasting action potentials (AP) were considered as a separate subpopulation, in light of previous studies. To segregate the remaining 269 neurons, presumably dopaminergic (DA), we performed analyses, using a combination of different electrophysiological parameters. These parameters included: (1) firing rate; (2) firing rate coefficient of variation (CV); (3) percentage of spikes in a burst; (4) AP duration; (5) Δt duration (i.e., time from initiation of depolarization until end of repolarization); and (6) presence of a notched AP waveform. Unsupervised hierarchical clustering revealed two neuronal populations that differed in their bursting activities. The largest population presented low bursting activities (17.5%). Within non-high-firing neurons, a large heterogeneity was noted concerning AP characteristics. In conclusion, this analysis based on conventional electrophysiological criteria clustered two subpopulations of putative DA VTA neurons that are distinguishable by their firing patterns (firing rates and bursting activities) but not their AP properties

Examining techniques for measuring the effects of nutrients on mental performance and mood state

Purpose: Intake of specific nutrients has been linked to mental states and various indices of cognitive performance although the effects are often subtle and difficult to interpret. Measurement of so-called objective variables (e.g. reaction times) is often considered to be the gold standard for assessing outcomes in this field of research. It can, however, be argued that data on subjective experience (e.g. mood) are also important and may enrich existing objective data. The aim of this review is to evaluate methods for measuring mental performance and mood, considering the definition of subjective mood and the validity of measures of subjective experience. Methods: A multi-stakeholder expert group was invited by ILSI Europe to come to a consensus around the utility of objective and subjective measurement in this field, which forms the basis of the paper. Therefore, the present review reflects a succinct overview of the science but is not intended to be a systematic review. Results: The proposed approach extends the traditional methodology using standard ‘objective’ measurements to also include the consumers’ subjective experiences in relation to food. Specific recommendations include 1) using contemporary methods to capture transient mood states; 2) using sufficiently sensitive measures to capture effects of nutritional intervention; 3) considering the possibility that subjective and objective responses will occur over different time frames; and 4) recognition of the importance of expectancy and placebo effects for subjective measures. Conclusions: The consensus reached was that the most informative approach should involve collection and consideration of both objective and subjective data

Dietary polyphenol supplementation prevents alterations of spatial navigation in middle-aged mice

Spatial learning and memory deficits associated with hippocampal synaptic plasticity impairments are commonly observed during aging. Besides, the beneficial role of dietary polyphenols has been suggested as potential functional food candidates to prevent this memory decline. Indeed, polyphenols could potentiate the signaling pathways of synaptic plasticity underlying learning and memory. In this study, spatial learning deficits of middle-aged mice were first highlighted and characterized according to their navigation patterns in the Morris water maze task. An eight-week polyphenol-enriched diet, containing a polyphenol-rich extract from grape and blueberry (PEGB; from the Neurophenols Consortium) with high contents of flavonoids, stilbenes and phenolic acids, was then successful in reversing these age-induced effects. The use of spatial strategies was indeed delayed with aging whereas a polyphenol supplementation could promote the occurrence of spatial strategies. These behavioral results were associated with neurobiological changes: while the expression of hippocampal calmodulin kinase II (CaMKII) mRNA levels was reduced in middle-aged animals, the polyphenol-enriched diet could rescue them. Besides, an increased expression of nerve growth neurotrophic factor (NGF) mRNA levels was also observed in supplemented adult and middle-aged mice. Thus these data suggest that supplementation with polyphenols could be an efficient nutritional way to prevent age-induced cognitive decline